The autism spectrum disorders. (ASD) are a group of serious neurodevelopmental disorders characterized by deficits in communication, abnormal social interactions, and rigid or repetitive interests and behaviors. Although there is strong evidence of an important genetic contribution to the cause of ASD, the isolation of specific causative genetic defects has been difficult. This project will use existing DNA and clinical data from the ACRE and NIMH repositories to search for ASD susceptibility genes. Aim 1 will focus on the analysis of genotype data using an alternative, Bayesian approach to linkage analysis, based on the posterior probability of linkage (PPL). This method was selected as the main analysis approach as it has been demonstrated to be far more effective in extracting accurate information from gene-mapping studies of heterogeneous disorders than any of the current model-based or model-free alternatives, greatly aiding the localization of susceptibility genes. Aim 2 will focus on fine linkage and linkage disequilibrium mapping of regions identified in Aim 1. PPL linkage peaks will initially be narrowed through 1-2 cM density microsatellite mapping, followed by very high density SNP mapping. SNP genotyping will be conducted using an inexpensive, robust, flexible and scalable genotyping system based on allele-specific ligation. An extension of the PPL that incorporates Linkage Disequilibrium (LD) will be used for LD mapping of candidate genes within the linkage peaks. Aim 3 will investigate whether associated haplotypes functionally alter the candidate genes using lymphoblastoid and post-mortem samples as well as in vitro neuronal cultures and mouse knock-ins to analyze developmentally relevant cell types. Upon completion of these experiments, it is likely that ASD-associated alleles for multiple genes will be identified. Through our extensive functional analysis, we will be able to demonstrate that some of the associated haplotypes functionally alter the associated genes, making them likely candidates for risk alleles and providing genetic evidence that these genes likely act as ASD susceptibility loci. The mouse models that will be generated for some of these associated haplotypes will provide a more amenable system for future developmental, behavioral and toxicology experiments. These accomplishments will lead to important translational research so that better diagnoses, treatments and preventions can be developed for ASD.